Case study
I am a 48-year old woman with secondary progressive MS that was started on Siponimod 6 months ago. Unfortunately, I have had two seizures and have now been diagnosed with epilepsy. My neurologist started me on lamotrigine and it caused me to go off my legs. Two days after starting lamotrigine I couldn’t get out of bed; my legs collapsed under my weight. I have an EDSS 6.5 and use a walker in the house and a wheelchair for outdoor mobility. What would you recommend?
Prof G’s advice
As you know MS is not only a disease of white matter. About half the lesion burden of MS is in the grey matter the part of the brain where seizures start.
Seizures and epilepsy are not uncommon in MS, particularly in people with more advanced MS. About 15-20% of pwSPMS go on to develop recurrent seizures or epilepsy and require anticonvulsants. It is interesting that this person developed epilepsy after starting siponimod. This is one of the well-known side effects of siponimod that was seen in the phase 3 trial and is probably a class effect of the S1P modulators as it has been noticed with fingolimod as well, particularly in the paediatric fingolimod MS trial.
I suspect this woman had an abnormal EEG hence the decision by her neurologist to start an anticonvulsant and to continue the siponimod. This makes sense to me. At the moment we only have one licensed treatment for SPMS and if the siponimod is stopped this patient wouldn’t have any other DMT options outside of clinical trials.
It is noteworthy that this patient was started on lamotrigine, a so-called sodium-channel blocker, that caused her legs to give way. This is called the rag-doll syndrome and happens when pwMS are using the stiffness or spasticity in their legs to support them. If you then give them a therapy that reduces spasticity their legs give way and they cannot walk. Sodium channel blockers may actually block vulnerable nerve fibres that are only just working thereby exacerbating weakness.
In my experience, sodium channel blockers are the worst class of drugs for causing the ragdoll effect. This is very unfortunate as there is good evidence that sodium channel blockers may be neuroprotective in MS. We have good preclinical data and data from clinical trials in MS to support this. One of the add-on neuroprotective trials we did was with lamotrigine SPMS. In this trial, about 40% of study subjects could not tolerate lamotrigine because of side effects such as the ragdoll effect experienced by this patient.
When you demyelinate a nerve fibre it recovers function by a process of axonal plasticity or remyelination. Axonal plasticity is when the nerve fibre inserts new sodium channels along the demyelinated segment to restore nerve conduction. These axonal segments have a markedly reduced safety factor of conduction and conduction is easily blocked in them by subtle changes in temperature, with exercise and in response to drugs that affect nerve conduction.
The following videos show you what normal conduction looks like and how slow conduction is in a demyelinated nerve fibre. You get a sense of how difficult it is for pwMS to conduct electrical impulses down damaged nerves and the amount of energy that is required to do it. This is why pwMS get so tired when doing any exercise or activity that requires increasing the workload of the damaged nerve fibres. I suspect this lady also has problems with both temperature and exercise-induced conduction block. You also get a sense that she is not far off from needing a wheelchair indoors as well.
Please note that this lady would be sensitive to all anti-spasticity drugs. The rag-doll syndrome does not only occur with sodium channel blockers.
My recommendation for this patient would be to avoid any anticonvulsants that may affect muscle tone, i.e. the stiffness of the muscles. This is very difficult as most anticonvulsants affect spasticity. The two anti-convulsants that may be worth trying are levetiracetam and failing that sodium valproate. I would start with a low dose of levetiracetam and build up the dose very slowly, i.e. I would start with 250mg at night and increase the dose by 250mg per day every week or two until she was on 500mg twice a day. This is quite a low dose of levetiracetam and it could be increased further. In my experience, the ragdoll syndrome can sometimes be avoided by slow titration of medication.
Please note because sodium valproate or valproic acid is teratogenic (causes foetal development problems) neurologists don’t use it much anymore. However, as this patient is almost certainly beyond childbearing it is an anticonvulsant that could be very effective in this situation.
As siponimod is metabolised primarily by a group of liver enzymes called cytochromes it is susceptible to drug-drug interactions. It is important if you are on siponimod and need to start a new drug that you check that there are no documented or potential drug-drug interactions. I have checked and both levetiracetam and valproic acid are fine to take in combination with siponimod.
I think this case illustrates the complexities of dealing with comorbidities in more advanced MS. One thing I would do in this patient is an MRI of the brain. Yes, MS and/or siponimod is the most likely cause of her seizure and epilepsy it is important to exclude other pathologies. Yes, pwMS also get brain tumours, have strokes, brain haemorrhages, develop PML and other pathologies that can present with seizures.
Clearly, this patient is vulnerable and as part of the routine consultation, she should be advised about not driving, notifying the DVLA or driving authority in her country and given advice about safety, i.e. not bathing alone, etc. As she is at risk of falls and fractures she needs to attend a falls prevention clinic, have her bone density checked and start on therapy if she is found to have thin bones (osteopaenia or osteoporosis). The last thing this lady needs is to have a seizure and a fall and fracture her femur or another long bone.
I would be interested to hear if any of you have had the rag-doll syndrome and how you have managed it.
In some parts of the world, typically high-income countries, pwMS are beginning to start using exoskeletons to keep them mobile and walking. I have little doubt that exoskeletons will be commonplace in the management of MS in the near future.
Subscriptions
As you are aware I am raising funds from paid subscriptions to administer the MS-Selfie Newsletter and associated MS-Selfie microsite that is currently in development. So if you are an active paying subscriber thank you, your contribution is much appreciated.
I originally charged a subscription for case studies such as this and made all the other MS-Selfie newsletters free. I subsequently changed the funding model of MS-Selfie and made all content free. However, since doing this I have had a large number of subscribers cancel their subscriptions, which is now threatening the financial viability of MS-Selfie. If this trend continues, which I hope it will not, I will have to reintroduce a two-tiered system with the case studies being restricted to paying subscribers only.
Please note the money raised via subscriptions is being used to pay a professional medical writer to curate, rewrite and transfer the contents of the Newsletter onto a companion MS-Selfie microsite, which is being designed and maintained by a freelance web designer.
So if you find these Newsletters helpful and want the wider MS community to continue to have access to all content I would encourage you to become a paid subscriber. Thank you.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.
The rag-doll effect